autonomics parasympathetic
TRANSCRIPT
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AutonomicsAutonomics
Claro M. Isidro M.D.
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Parasympathetic DrugsParasympathetic Drugs
Drugs Affecting the ANS:
1.Cholinergic drugs – act on the receptor that is activated by acetylcholine
2.Adrenergic drugs – acts on the receptor that are stimulated by norepinephrine or epinephrine
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Cholinergic NeuronsCholinergic Neurons
Preganglionic fibers terminating in the adrenal medulla
Preganglionic fibers of both parasympathetic & sympathetic nervous system
Postganglionic fibers of the parasympathetic nervous system
Voluntary muscles of the somatic nervous system
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Neurotransmission at Cholinergic neurons
Synthesis of acetylcholineStorage of acetylcholine in vesiclesRelease of acetylcholineBinding to receptorDegradation of acetylcholineRecycling of choline
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Cholinergic Receptors Muscarinic : M1 – nerves M2 – heart, nerves, smooth muscles M3 – glands, smooth muscles Endothelium M4 - ? CNS M5 - ? CNS
Nicotinic: Nm – skeletal muscles Neuromuscular junction Nn – Preganglionic parasympathetic & sympathetic
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Effector Organs Receptors Action
Eye sphincter m.
ciliary m.
M3
M3
Contraction (meiosis)Contraction(accomodation)
Heart SA node AV node Contractility
M2
M2
M2
↓ Heart rate
↓ conduction velocity & ↑ refractory period
↓ contraction
Lung bronchial m. M3 contraction
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Effector Organs Receptor Action
Blood Vessels most BV skeletal m.
--
Small doses – vasodilatation Large doses – vasoconstriction
GIT sphincter motility & tone
M3
M3
RelaxationIncrease
GUT trigone & sphincter m. bladder wall & detrusor m.Penis, seminal v.
M3
M3
M
Relaxation
Contraction
Erection
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Effector Organs
Receptor Action
Secretory glands sweat intestinal bronchial lacrimal
M
M3
MM
Generalized secretion↑ secretion↑ secretionProfuse secretion
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Cholinomimetics / Parasympathetic Agonist/Cholinergic Agonist Drugs that have effects producing parasympathetic dominance
Direct-Acting Cholinoceptor Stimulants
A. Esters of Choline: Synthetic
1. Acetylcholine 3. Carbachol
2. Metacholine 4. Betanechol
B. Alkaloids: Naturally occurring
1. Muscarinic
Muscarine, Pilocarpine, Oxotremorine
2. Nicotinic
Nicotine, Lobeline,
Dimethylphenylpiperazinium (DMPP)
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Direct-Acting (Choline Esters)::
Acetylcholine quarternary ammonium compound muscarinic & nicotinic receptors equally Actions:
↓ HR and CO, ↓ BP ↑ salivary & intestinal secretion and GI motility Enhances bronchiolar secretions ↑ detrussor muscle tone stim. Ciliary m. → near vision miosis
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Susceptibility to
Cholinesterase
Muscarinic Effects
Nicotinic Effects
Therapeutic Use
Ach + +++ +++ Miotic
Metacholine
+ ++++ + Dx of bronchial hyperactivity
Carbachol - +++ ++ Miotic
Betanechol - ++ - Non-obstructive urinary retention
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Direct-Acting (Choline Esters):
Naturally-occurring:
Pilocarpine• tertiary amine
• dominant muscarinic action• resistant to acetylcholinesterase• Use as topical eye drop. Produce rapid meiosis & contraction of
ciliary muscle• Increase gastric acid secretion & bronchoconstiction• Potent stimulator of secretions (sweat, tears, saliva)• Therapeutic Use:
• DOC in emergency lowering of IOP in glaucoma• Adverse Effects: CNS disturbances, profuse sweating and salivation
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ARECOLINE• chief alkaloid of areca or betel nuts• muscarinic & nicotinic receptors• enhances salivary secretion• no therapeutic indication
MUSCARINE• quarternary amine• muscarinic receptors• found in mushrooms (Amanita muscaria)• small amounts edible• large amounts poisonous• effects: fall in BP, temporary cessation of heart beat,
diaphoresis• antidote: ATROPINE
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Indirect-Acting : AnticholinesteraseIndirect-Acting : Anticholinesterase
REVERSIBLE (Anticholinesterases)
IRREVERSIBLE (Organophosphate)
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AnticholinesteraseAnticholinesterase
AcetylCholine Choline + Acetic acid
Cholinesterase-
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Indirect-Acting :REVERSIBLE (Anticholinesterases):
Physostigmine Neostigmine Pyridostigmine Ambenonium Edrophonium Tacrine, Donezepil, Rivastigmine, Galantamine
IRREVERSIBLE1. Organophosphates
• Isoflurophate• Echothiophate• Malathion, Parathion
2. Chemical Warfares• Sarin, Soman
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PHYSOSTIGMINE• Alkaloid, tertiary ammmonium grp.• Enters the CNS• DOA: O.5 to 2 hrs.• Therapeutic Uses:
1. Atony of intestines and bladder2. Glaucoma lowers IOP3. Antidote atropine, phenothiazines, TCA4. NDMR (tubocurarine) reversal
• Adverse effects: convulsions, bradycardia, CO
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NEOSTIGMINE• Quarternary ammonium grp.• Does not enter the CNS peripheral• DOA: 0.5 to 2 hrs• Therapeutic Uses:
1. Atony of intestines and bladder2. Myasthenia gravis3. NDMR (tubocurarine) antidote
• Adverse effects: salivation, flushing, ↓ BP, nausea, abdominal pain, diarrhea, bronchospasm
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PYRIDOSTIGMINE and AMBENONIUM
• DOA: PYRIDOSTIGMINE - 3 to 6 hrs• AMBENONIUM – 4 to 8 hrs• Therapeutic Uses:
1. Myasthenia gravis2. NDMR (tubocurarine) antidote
• Adverse effects: salivation, flushing, ↓ BP, nausea, abdominal pain, diarrhea, bronchospasm
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EDROPHONIUM • Quarternary amine• DOA: 5 to 15 mins• Therapeutic Uses:
1. Diagnosis of Myasthenia gravis2. NDMR (tubocurarine) antidote3. Arrhythmias (SVT)
• Antidote: Atropine• Adverse effects: salivation, flushing, ↓ BP, nausea,
abdominal pain, diarrhea, bronchospasm
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Tacrine, Donezepil, Rivastigmine,Galantamine
• Alzheimer disease deficiency of cholinergic neurons in the CNS
• Tacrine – hepatotoxic• Adverse effect: GI distress
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Indirect-Acting IRREVERSIBLE : ORGANOPHOSPHATES
ISOFLUROPHATE tx of open angle glaucoma
ECHOTHIOPHATE Produce intense miosis tx of open angle glaucoma
PARATHION, MALATHION Insecticides
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ORGANOPHOSPHATE POISONING:
Signs & Symptoms1. miosis2. salivation, frothy secretions3. sweating4. bronchial constriction5. vomiting and diarrhea6. muscle fasciculation
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ORGANOPHOSPHATE POISONING:
Therapy:• maintenance of VS respiration• Decontamination• Drugs: Atropine + Pralidoxime ATROPINE sulfate
• 1 to 2 mg IV every 5-15 min until muscarinic effect disappears (maximum of 1 gm per day)
PRALIDOXIME
• A cholinesterase enzyme regenerator compound
• - 1 to 2 gm given over 30 min by IV infusion
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Parasympathetic Antagonists/Cholinergic Antagonist (Parasympatholytics)
ANTIMUSCARINIC
Tertiary Amines:a. Natural – atropine, scopolamine
b. Semisynthetic – tropine, homatropine
c. Synthetic – dicyclomine, oxybutyrine, oxyphencyclimine
Quarternary Amines:a. Anisotropine
b. Propantheline
c. Methanteline
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ATROPINE• prototype• Belladona alkaloid• high affinity for muscarinic receptors• central and peripheral muscarinic blocker
causes reversible (surmountable) blockade of the actions of cholinomimetics at muscarinic receptors
Unopposed sympathetic action
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ATROPINEActions:1. CNS
• minimal stimulant effect2. Eye
• mydriasis, unresponsiveness to light• cycloplegia inability to focus for near-vision
3. GIT• antispasmodic reduce GIT activity
4. GUT • reduce urinary bladder hypermotility
5. SECRETIONS• blocks salivary glands antisialogogue• decrease also lacrimal & sweat glands secretion
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ATROPINE
6. CVSdivergent effects depending on
dose
Low dose – (-) M1 ↑ Ach release
Higher dose – (-) M2 on SA node ↑ CR
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Effects in relation to dose:
Dose Effects
0.5 mg Slight cardiac slowing some dryness of mouth inhibition of sweating
1.0 mg Definite dryness of mouth; thirst acceleration of heart, sometimes preceded by slowingmild pupillodilatation
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Dose Effects
2.0 mg Rapid HR; palpitations marked dryness of mouth Dilated pupils; some blurring of vision
5.0 mg All of the above symptoms marked; difficulty in speaking and swallowing;Restlessness and fatigue;Headache; dry, hot skinDifficulty in micturitionReduced intestinal peristalsis
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Dose Effects
10.0 mg and more Above symptoms more markedPulse rapid and weakIris practically obliteratedVision very blurredSkin flushed, hot, dry, and scarletAtaxia, restlessness and excitementHallucinations and deliriumComa
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ATROPINETherapeutic Uses:1. Ophthalmic
• Permits measurement of EOR
2. Antispasmodic3. Antidote for cholinergic agonists
• Organophosphate poisoning• Mushroom poisoning• acetylcholinesterase inhibitors
4. Antisecretory agent
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SCOPOLAMINE• Belladona alkaloid• Peripheral effects similar to atropine• Greater and longer CNS action• Action:
• Anti-motion sickness• Blocks short-term memory• Produces sedation, • excitement
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Therapeutic Uses: anti-motion sickness adjunct in anesthesia procedures > in obstetrics, + morphine sedation & amnesia
IPRATROPIUM• Quarternary derivative of atropine• Does not enter CNS • Therapeutic Uses:
• Treat asthma in patients who are unable to take adrenergic agonists
• Management of COPD
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GANGLIONIC BLOCKERS
Specifically act on NICOTINIC receptors No selectivity towards PNS or SNS Blocks entire ANS output
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GANGLIONIC BLOCKERSA. NICOTINE
B. TRIMETHAPHAN
C. MECAMYLAMINE
D. HEXAMETHONIUM
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The End
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Write A if cholinergic agonist
B if cholinergic antagonist
1. Bethanicol
2. Scopolamine
3. Isoflurophate
4. Trimethaphan
5. Arecoline
6. Main neurotransmitter of PNS
7. Amino acid precursor of Ach
8. Drug of choice in emergency lowering of IOP
9. Antidote for organophosphate poisoning
10. Aids in the diagnosis of myasthenia gravis
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Short QuizShort Quiz
1. Describe the pharmacodynamic difference between direct and indirect acting cholinomimetics
2. Describe the effects of acetylcholine on the major organs
3. Describe the effects of atropine on the major organ system
4. Clinical uses of atropine & scopolamine
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A. NICOTINE Low dose :
ganglionic stimulation by depolarization CNS: euphoria, arousal, relaxation
improves attention, learning, problem solving & reaction time
Peripheral: ↑ BP & HR, vasoconstriction
High dose ganglionic blockade BP falls, blocks GIT & bladder activity